Researchers grappling to understand what happens inside brain cells of people with Parkinson’s disease are baffled by a mystery that plays out as the disease progresses. Why is it that one group of neurons decays while a similar group nearby remains unscathed?

The two proteins – SATB1 and ZDHHC2 – appear to protect the brain cells most affected by Parkinson’s disease. When the proteins become less active, the disease sets in.

Scientists believe the causes of Parkinson’s disease center around what are called dopaminergic neurons. These cells release the messenger molecule dopamine, a chemical that is important for control of movement.

The dopamine-releasing cells most affected by Parkinson’s disease are located in a midbrain region called the substantia nigra pars compacta (SNpc). As the disease progresses, these cells gradually deteriorate and die.

The researchers – whose study focuses on molecular changes in dopamine-releasing cells – suggest their discovery could lead to new targets for drugs that slow the progression of Parkinson’s disease.

Researchers searched ‘translatome’ as opposed to genome
The study is also significant for another reason – the molecular searching method that the team used to find the two proteins.

Usually, when scientists want to look for molecular changes that affect disease, they use genetic sequencing to create a profile of the variations in gene expression.

But gene expression profiling is not a very useful tool when you are trying to identify the molecular changes that occur in a particular type of cell and focus on the really important ones.

Also, genes do not act in a straightforward manner – they also regulate each other. There are master regulator genes that act as control dials, turning other genes on and off, or up and down. Gene expression profiling does not easily tell you about the molecular changes that arise from gene expression.

To overcome this difficulty, the team adapted a method that some of the members had already been working on – one that searches the “translatome” as opposed to the genome – to find the proteins involved in communicating changes arising from master regulator genes.

The translatome is the complete collection of messenger molecules that are involved with translating genetic information from DNA and carrying it to sites where proteins are made inside cells.

With genetically engineered mice, the team captured the genetic messages being translated into proteins in dopaminergic neurons in the mice’s midbrain region.

They then compared the interactions of regulator genes with their target genes in the mouse brain, and used this map to interpret the changes they found between normal mice and those with Parkinson’s-like symptoms.

“Within a dying nerve cell, the levels of hundreds of proteins change. Some of these shifts are consequences, others are causes. We set out to find which cause cell death among neurons.”

Discovery explains why one group of dopamine cells is more affected
Their new approach helped the team find two of the so-called master regulatory molecules. Prof. Greengard says the discovery offers an “unexpected explanation as to why one population of neurons degenerates in Parkinson’s, while similar neighbors do not suffer from the same degree of degeneration.”

While the dopamine-producing neurons of the SNpc are the ones most affected by Parkinson’s disease, there is another group of dopamine-producing neurons in another region called the ventral tegmental area (VTA) that is less affected.

The team found that the two proteins SATB1 and ZDHHC2 are more abundant in the dopaminergic neurons in the SNpc than in the VTA.

When the researchers reduced the abundance of these molecules in the brains of normal mice, they observed it was followed by rapid degeneration like that seen in Parkinson’s disease.

The team believes conventional gene expression profiling would not have been able to identify the two proteins as key protective factors. Even though they continue to be expressed in the neurons, their regulatory activity drops off and they no longer stimulate their target genes, says first author Lars Brichta, a senior research associate in Greengard’s lab, who adds:

“We later found similar changes in activity in the brains of Parkinson’s patients, particularly those in the early stages.”
The findings also challenge current thinking about the molecular origins of Parkinson’s disease, where it is thought that the VTA neurons are protected in some way by the decay seen in neurons of the SNpc. But, Greengard asserts:

“In an unexpected contradiction to current models, the proteins we found protect the SNpc. Because dopamine and its metabolites can be toxic, we can speculate that, in the course of evolution, SATB1 and ZDHHC2 arose to protect this particular set of sensitive neurons from cell death.”

As well as opening a route to new treatments for Parkinson’s disease, the team believes their translatome approach may also be useful in the study of other neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and Huntington’s disease.

Meanwhile, Medical News Today recently learned that a liver disease drug could slow Parkinson’s disease. A paper in the journal Neurology, describes how ursodeoxycholic acid (UDCA) – a drug that has long been used to treat liver disease – has beneficial effects on fruit fly nerve cells with mutations in the LRRK2 gene, the most common inherited cause of Parkinson’s disease.